The compound 2-methyl-1,2-hexanediol characterized by the structural formula: ##STR1## is an intermediate in the syntheses of several prostaglandins that are useful for peptic ulcer therapy.
In this respect Collins (J. Medic. Chem. 29[4], 437 [1986]) states that four synthetic prostaglandins which contain a 4-hydroxy-4-methyl-1(E)-octenyl group as the substituent at position 3 of the cyclopentanone are in clinical use for peptic ulcer therapy.
The first of these four prostaglandins is (.+-.)-4.alpha.-hydroxy-3.beta.(4RS)-[4-hydroxy-4-methyl-1(E)-octenyl]-2.a lpha.-[6-carbomethoxyhexanyl]-cyclopentanone characterized by the structural formula: ##STR2##
The second of these four prostaglandins is 4.alpha.-hydroxy-3.beta.-(4RS)--[4-hydroxy-4-methyl-1(E)-octenyl]-2.alpha. -[7-hydroxyheptanyl]cyclopentanone characterized by the structure formula: ##STR3##
The third of these four prostaglandins is (.+-.)-4.alpha.-hydroxy-3.beta.-(4RS)-[4-hydroxy-4-methyl-1(E)-octenyl]-2. alpha.-[7-oxo-8-hydroxyoctanyl]cyclopentanone characterized by the structural formula: ##STR4##
The fourth of these four prostaglandins is (.+-.)-4.alpha.-hydroxy-3.beta.-(4RS)-[4-hydroxy-4-methyl-1(E)-octenyl]-2. alpha.-[6-carbomethoxy-3(Z)-hexenyl]cyclopentanone characterized by the structural formula: ##STR5##
Collins (J. Medic. Chem. 29[4], 437 [1986]) also states that the four synthetic prostaglandins whose structural formulae are given above are in clinical use as mixtures of stereoisomers since the preparation of a single stereoisomer is complicated by the fact that chromatographic separation of prostaglandin mixtures of stereoisomers in the 16-methyl-16-hydroxy series is difficult and cannot be done at a practical scale.
However, it is well known in the art that the most active synthetic prostaglandin analogues are those that have a specific stereochemistry at each quiral center.
Collins (J. Medic. Chem. 29[4], 437 [1986]) further states that the major process for the preparation of the four compounds whose structural formulae are given above consists of a 1,4 conjugate addition of an organometallic compound characterized by the structural formula: ##STR6## to a cyclopentenone of the general formula: ##STR7## where R is a protecting group and R.sub..alpha. is the desired "alpha chain", and that therefore the effective ways in which a single stereoisomer of these prostaglandins can be obtained, is by resolution of both the desired substituted cyclopentenone and of the "omega chain", which means the precursor of the organometallic compound whose structural formula is given above, or by a combination of resolution of stereoisomers and synthetic asymmetric induction.
Collins continues to state that although reasonably efficient methods have been developed to resolve the desired substituted cyclopentenones, no good method has been found to resolve 4-hydroxy-4-methyl-1-octyne, characterized by the structural formula: ##STR8## which is then converted into the organometallic compound whose structural formula is given above.
In turn, 4-hydroxy-4-methyl-1-octyne is prepared from 2-methyl-1, 2-hexanediol whose structural formula is given above.
Thus, development of a convenient method to prepare individual stereoisomers of 2-methyl-1,2-hexanediol will lead to a substantial reduction of the clinical doses of the four synthetic prostaglandins whose structural formulae are given above.
Various methods have been developed for the preparation of a given individual stereoisomer of 2-methyl-1,2-hexanediol. Most of these methods and their disadvantages have been summarized by Corey (U.S. Pat. No. 4,633,025 issued Dec. 30, 1986, and U.S. Pat. No. 4,668,822 issued May 26, 1987) who also teaches the preparation of individual stereoisomers of 2-methyl-1,2-hexanediol and of 2-hydroxy-2-methylhexanoic acid. The latter, by reduction, also provides 2-methyl-1,2-hexanediol. The disadvantage of these methods of Corey is that long multi-step sequences of reactions are necessary for the preparation of the desired stereoisomers of 2-methyl-1,2-hexanediol.
The invention described herein teaches short methodology for the preparation of (+)-R-2-methyl-1,2-hexanediol and of (-)-S-2-methyl-1, 2-hexanediol. These compounds can subsequently be used for the preparation of individual stereoisomers of certain optically active prostaglandins such as those whose structural formulae are given above.